Functional characterisation of the CAG polymorphism in the androgen receptor- in vitro and in vivo

Research output: ThesisDoctoral Thesis (compilation)

Abstract

The androgen receptor (AR) is the mediator of androgen actions. In the AR coding region there is a polymorphic CAG repeat encoding a stretch of the amino acid glutamine (Q). The repeat length modulates receptor activity and is normally distributed between 10-30 CAG with a median length of 22 repeats in white men. At the start of this work, a negative linear association between AR function and the CAG repeat number was generally assumed. This assumption was supported by clinical findings in patients with Kennedy’s disease, which is a neuromuscular disorder caused by an abnormally expanded CAG repeat (>40 CAG). However, in vivo data concerning the association between CAG numbers within normal length and androgenic effects were conflicting. As understanding the impact of CAG number on the AR activity is important for proper interpretation of this polymorphism and risk of pathological conditions other than Kennedy’s disease, the purpose of this study was to examine the influence of CAG length, if any, on AR activity.
Firstly an in vitro study was performed. A reporter gene with a human androgen responsive promoter was used in a transactivation assay. The repeat lengths included were 16, 22 and 28 CAG, which represent a short, the median, and a long repeat within the normal human range. The study showed that the AR with median repeat length had the highest activity in vitro. Secondly, the effect of the CAG repeat in relation to two androgen dependent conditions, infertility and PCa, was analysed in two separate meta-analyses. When stratifying the CAG repeats into three groups, shorter than median, median and longer than the median CAG length, the meta-analysis on infertile men showed 20% increased risk of infertility in men harbouring other repeat lengths than the most common. On the other hand, CAG number did not have any effect on PCa risk.
The AR regulates the expression of prostate specific antigen (PSA). Thus the expression of PSA can be used as a marker of AR activity in tissue. We measured the AR protein and PSA amount in human prostate tissue from 19 men with known CAG length. Those who were carriers of 22 CAG had lower AR amount and higher PSA than counterparts with other CAG lengths, but this was not statistically significant, probably due to the small study size.
Taken together, these studies indicate that the median length of the androgen receptor CAG repeat is associated with optimal activity, in vitro and in vivo.

Details

Authors
  • Hannah Nenonen
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Clinical Medicine

Keywords

  • androgen receptor, polymorphism, CAG polymorphism, androgen receptor activity, infertility, prostate cancer, androgen receptor function
Original languageEnglish
QualificationDoctor
Awarding Institution
Supervisors/Assistant supervisor
Award date2011 Apr 1
Publisher
  • Department of Clinical Sciences, Lund University
Print ISBNs978-91-86671-75-4
StatePublished - 2011
Publication categoryResearch

Bibliographic note

Defence details Date: 2011-04-01 Time: 09:00 Place: Jubileumsaulan, Entrance 59, SUS, Malmö External reviewer(s) Name: Saunders, Philippa Title: Professor Affiliation: Centre for Reproductive Biology The Queen's Medical Research Institute Edinburgh, Scotland ---

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Related research output

Nenonen, H., Björk, C., Skjaerpe, P., Aleksander Giwercman, Lars Rylander, Svartberg, J. & Yvonne Giwercman, 2010, In : Molecular Human Reproduction. 16, p. 153-157

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